POSTTRANSCRIPTIONAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA 1

转化生长因子-BETA 1 的转录后调控

• 批准号: 3752650
• 负责人: L M WAKEFIELD
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752650
• 关键词: RNA splicing; blood proteins; complementary DNA; gene induction /repression; genetic manipulation; genetic regulation; genetic translation; growth inhibitors; hormone regulation /control mechanism; human subject; human tissue; messenger RNA; posttranscriptional RNA processing; protein biosynthesis; steroid hormone; tissue /cell culture; transcription factor; transfection; transforming growth factors

In many cell types there is a large discrepancy between the measured levels of transforming growth factor-beta (TGF-beta1) mRNA and protein. This suggests that translational or post-translational mechanisms play an important role in the regulation of TGF-beta1 production. Clinically important members of the steroid hormone superfamily affect both these processes. We have identified a novel upstream start site in the TGF- beta1 MRNA, and have investigated the effects of start site usage on translational regulation of the MRNA by generating constructs in which various portions of the 5' and 3' UTRs have been deleted. From the results of in vitro translation experiments, a gross map of the cis- acting elements that regulate the translational efficiency has been constructed. The 3' UTR consistently stimulates translation, while the 5' UTR contains both stimulatory and inhibitory elements. Selection of alternative transcriptional start sites determines which of these elements dominates, and allows translational efficiency of the TGF-beta1 MRNA to vary over a 16-fold range. Methodology has been developed for accurate measurement of TGF-betas in the plasma of human subjects. The antiestrogen, tamoxifen, which increases TGF-beta1 levels in the tumor stroma of women with breast cancer, has no effect on circulating TGF- beta1 levels. An understanding of the mechanisms whereby steroids and related compounds regulate the production and activity of the TGF-beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer.

在许多细胞类型中，所测量的 转化生长因子-β（TGF-β 1）mRNA和蛋白水平。 这表明，翻译或翻译后机制发挥作用， 在调节TGF-β 1的产生中起重要作用。 临床 类固醇激素超家族的重要成员影响这两个 流程. 我们已经确定了一个新的上游起始位点的TGF-β， β 1 mRNA，并研究了起始位点的使用对 通过产生构建体来调节mRNA的翻译，其中 5 ′和3 ′ UTR的多个部分已被删除。 从 体外翻译实验的结果，顺式- 调节翻译效率的作用元件已经被 构建了 3' UTR一贯地刺激翻译，而3' UTR则持续地刺激翻译。 5' UTR含有刺激和抑制元件。 选择 另一个转录起始位点决定了 元件占主导地位，并允许TGF-β 1的翻译效率 mRNA的变化范围超过16倍。 已经制定了方法， 准确测量人类受试者血浆中的TGF-β。 的 抗雌激素，他莫昔芬，增加肿瘤中的TGF-β 1水平 乳腺癌妇女的间质，对循环TGF-β没有影响。 beta1水平。 了解类固醇和 相关化合物调节TGF-β的产生和活性 生长抑制剂家族可以允许合理设计更有效的 用于化学预防或化学治疗 癌